Therapeutic compounds

ABSTRACT

Compounds of formula I: 
     
       
         
         
             
             
         
       
     
     or salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating a Retroviridae viral infection including an infection caused by the HIV virus.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 61/750,762, filed Jan. 9, 2013, the disclosure ofwhich is hereby incorporated by reference in its entirety.

BACKGROUND

Positive-single stranded RNA viruses comprising the Retroviridae familyinclude those of the subfamily Orthoretrovirinae and generaAlpharetrovirus, Betaretrovirus, Gamaretrovirus, Deltaretrovirus,Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human andanimal diseases. Among the Lentivirus, HIV-1 infection in humans leadsto depletion of T helper cells and immune dysfunction, producingimmunodeficiency and vulnerability to opportunistic infections. TreatingHIV-1 infections with highly active antiretroviral therapies (HAART) hasproven to be effective at reducing viral load and significantly delayingdisease progression (Hammer, S. M., et al.; JAMA 2008, 300: 555-570).However, these treatments do lead to the emergence of HIV strains thatare resistant to current therapies (Taiwo, B., International Journal ofInfectious Diseases 2009, 13:552-559; Smith, R. J., et al., Science2010, 327:697-701). Therefore, there is a pressing need to discover newantiretroviral agents that are active against emerging drug-resistantHIV variants.

SUMMARY

Provided herein are compounds and methods for the treatment of a viralinfection. One embodiment provides a compound of formula I:

wherein:

A is a 5-membered N-heteroaryl, wherein the 5-membered N-heteroaryl issubstituted with one Z¹ group and optionally substituted with one ormore (e.g., 1, 2 or 3) Z² groups;

R¹ is a bicyclic-heteroaryl or tricyclic-heteroaryl, wherein anybicyclic-heteroaryl, or tricyclic-heteroaryl of R¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³ groups;

R² is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R² isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁴groups;

Z¹ is selected from (C₃-C₈)alkyl, aryl, heteroaryl, hetereocycle andaryl(C₁-C₆)alkyl-, wherein any aryl, heteroaryl, hetereocycle andaryl(C₁-C₆)alkyl- of Z¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b) groups and wherein any(C₃-C₈)alkyl of Z¹ is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z^(1a) groups;

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, halogen,—CN, —OR_(n1), —OC(O)R_(p1), —OC(O)NR_(q1)R_(r1), —SR_(n1), —S(O)R_(p1),—S(O)₂OH, —S(O)₂R_(p1), —S(O)₂NR_(q1)R_(r1), —NR_(q1)R_(r1),—NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), —NR_(n1)CONR_(q1)R_(r1),—NR_(n1)S(O)₂R_(p1), —NR_(n1)S(O)₂OR_(p1), —NR_(n1)S(O)₂NR_(q1)R_(r1),NO₂, —C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1);

each Z^(1b) is independently selected from (C₁-C₆)alkyl and(C₃-C₅)carbocycle wherein any (C₁-C₆)alkyl and (C₃-C₅)carbocycle ofZ^(1b) is optionally substituted with one or more (e.g., 1, 2, 3, 4 or5) halogen;

each Z² is independently selected from (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,halogen and —O(C₁-C₃)alkyl;

each Z³ is independently selected from (C₁-C₆)alkyl, (C₃-C₇)carbocycle,halogen, —CN, —OR_(n2), —OC(O)R_(p2), —OC(O)NR_(q2)R_(r2), —SR_(n2),—S(O)R_(p2), —S(O)₂OH, —S(O)₂R_(p2), —S(O)₂NR_(q2)R_(r2),—NR_(q2)R_(r2), —NR_(n2)COR_(p2), —NR_(n2)CO₂R_(p2),—NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2), —NR_(n2)S(O)₂OR_(p2),—NR_(n2)S(O)₂NR_(q2)R_(r2), NO₂, —C(O)R_(n2), —C(O)OR_(n2) and—C(O)NR_(q2)R_(r2), wherein any (C₃-C₇)carbocycle and (C₁-C₆)alkyl of Z³is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)halogen;

each Z⁴ is independently selected from (C₁-C₆)alkyl, halogen and—OR_(n), wherein any (C₁-C₆)alkyl of Z⁴ is optionally substituted withone or more (e.g., 1, 2, 3, 4 or 5) halogen;

each R_(n1) is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle;

each R_(p1) is independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl and (C₃-C₇)carbocycle;

R_(q1) and R_(r2) are each independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle, or R_(q1) andR_(r2) together with the nitrogen to which they are attached form a 5, 6or 7-membered heterocycle;

each R_(n2) is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle;

each R_(p2) is independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl and (C₃-C₇)carbocycle;

R_(q2) and R_(r2) are each independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle, or R_(q2) andR_(r2) together with the nitrogen to which they are attached form a 5, 6or 7-membered heterocycle; and

each R_(n3) is independently selected from H, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, and (C₃-C₇)carbocycle;

or a salt thereof;

provided the compound is not2-(1,3-dioxoisoindolin-2-yl)-N-(2-phenyl-1-(4-phenyloxazol-2-yl)ethyl)acetamide.In certain embodiments, a salt is a pharmaceutically acceptable salt.

One embodiment provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

One embodiment provides a method for treating a Retroviridae viralinfection (e.g., an HIV viral infection) in a mammal (e.g., a human),comprising administering a compound of formula I, or a pharmaceuticallyacceptable salt thereof, to the mammal.

One embodiment provides a method for inhibiting the proliferation of theHIV virus, treating AIDS or delaying the onset of AIDS or ARC symptomsin a mammal (e.g., a human), comprising administering a compound offormula I, or a pharmaceutically acceptable salt thereof, to the mammal.

One embodiment provides a method for treating an HIV infection in amammal (e.g., a human), comprising administering a compound of formulaI, or a pharmaceutically acceptable salt thereof, to the mammal.

One embodiment provides a method for treating an HIV infection in amammal (e.g., a human), comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of formula I,or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof.

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof for use in medical therapy (e.g., for use intreating a Retroviridae viral infection (e.g., an HIV viral infection)or the proliferation of the HIV virus or AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human)).

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof for use in the manufacture of a medicament fortreating a Retroviridae viral infection (e.g., an HIV viral infection)or the proliferation of the HIV virus or AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human).

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof, for use in the prophylactic or therapeutictreatment of the proliferation of a Retroviridae virus, an HIV virus orAIDS or for use in the therapeutic treatment of delaying the onset ofAIDS or ARC symptoms.

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof, for use in the prophylactic or therapeutictreatment of a Retroviridae virus infection (e.g., an HIV virusinfection).

One embodiment provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for a Retroviridae virus infection (e.g., an HIV virusinfection) in a mammal (e.g., a human).

One embodiment provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula I or salts thereof.In certain embodiments, a salt is a pharmaceutically acceptable salt.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceonly and are not to be construed to limit the claims in any way.Embodiments illustrated under any heading may be combined withembodiments illustrated under any other heading.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Alkyl” is a straight or branched saturated hydrocarbon. For example, analkyl group can have 1 to 8 carbon atoms (i.e., (C₁-C₅)alkyl) or 1 to 6carbon atoms (i.e., (C₁-C₆ alkyl) or 1 to 4 carbon atoms. Examples ofsuitable alkyl groups include, but are not limited to, methyl (Me,—CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl(—(CH₂)₇CH₃).

“Alkenyl” is a straight or branched hydrocarbon with at least one siteof unsaturation, e.g. a carbon-carbon, sp² double bond. For example, analkenyl group can have 2 to 8 carbon atoms (i.e., C₂-C₈ alkenyl), or 2to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examples of suitable alkenylgroups include, but are not limited to, ethylene or vinyl (—CH═CH₂),allyl (—CH₂CH═CH₂) and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a straight or branched hydrocarbon with at least one siteof unsaturation, i.e. a carbon-carbon, sp triple bond. For example, analkynyl group can have 2 to 8 carbon atoms (i.e., C₂-C₈ alkyne,), or 2to 6 carbon atoms (i.e., C₂-C₆ alkynyl). Examples of suitable alkynylgroups include, but are not limited to, acetylenic (—C≡CH), propargyl(—CH₂C≡CH), and the like.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms are each replaced by a halosubstituent. For example, a (C₁-C₆)haloalkyl is a (C₁-C₆)alkyl whereinone or more of the hydrogen atoms have been replaced by a halosubstituent. Such a range includes one halo substituent on the alkylgroup to complete halogenation of the alkyl group.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, an aryl group can have 6 to 20carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Arylincludes a phenyl radical. Aryl also includes multiple condensed ringsystems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9to 20 carbon atoms in which at least one ring is aromatic and whereinthe other rings may be aromatic or not aromatic (i.e., carbocycle). Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of themultiple condensed ring system. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that thepoint of attachment of a multiple condensed ring system, as definedabove, can be at any position of the ring system including an aromaticor a carbocycle portion of the ring. Typical aryl groups include, butare not limited to, phenyl, indenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

“Arylalkyl” refers to an alkyl radical as defined herein in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with an arylradical as described herein (i.e., an aryl-alkyl-moiety). The alkylgroup of the “arylalkyl” can be 1 to 6 carbon atoms (i.e.,aryl(C₁-C₆)alkyl). Arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl,2-naphthylethan-1-yl and the like.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; the term also includes multiple condensed ring systems that haveat least one such aromatic ring, which multiple condensed ring systemsare further described below. Thus, the term includes single aromaticrings of from about 1 to 6 carbon atoms and about 1-4 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in therings. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Such rings include but are notlimited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term alsoincludes multiple condensed ring systems (e.g., ring systems comprising2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can becondensed with one or more rings selected from heteroaryls (to form forexample a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (toform for example a 1,2,3,4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has about 1-20 carbonatoms and about 1-6 heteroatoms within the heteroaryl ring. Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the condensed ring. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the multiple condensedring system including a heteroaryl, heterocycle, aryl or carbocycleportion of the multiple condensed ring system and at any suitable atomof the multiple condensed ring system including a carbon atom andheteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are notlimited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl,thianaphthenyl, triazolyl, isoxazolyl, 4,5,6,7-tetrahydro-indazolyl andpyrrolo[3,2-b]pyridinyl.

The term “N-heteroaryl” refers to a heteroaryl that contains at leastone nitrogen atom within the ring system.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxogroups and the sulfur and nitrogen atoms may also be present in theiroxidized forms. Such rings include but are not limited to azetidinyl,tetrahydrofuranyl or piperidinyl. The term “heterocycle” also includesmultiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4rings) wherein a single heterocycle ring (as defined above) can becondensed with one or more groups selected from heterocycles (to formfor example a decahydronapthyridinyl), carbocycles (to form for examplea decahydroquinolyl) and aryls to form the multiple condensed ringsystem. Thus, a heterocycle (a single saturated or single partiallyunsaturated ring or multiple condensed ring system) has about 2-20carbon atoms and 1-6 heteroatoms within the heterocycle ring. Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the multiple condensed ring. The rings of the multiplecondensed ring system can be connected to each other via fused, spiroand bridged bonds when allowed by valency requirements. It is to beunderstood that the individual rings of the multiple condensed ringsystem may be connected in any order relative to one another. It is alsoto be understood that the point of attachment of a multiple condensedring system (as defined above for a heterocycle) can be at any positionof the multiple condensed ring system including a heterocycle, aryl andcarbocycle portion of the ring. It is also to be understood that thepoint of attachment for a heterocycle or heterocycle multiple condensedring system can be at any suitable atom of the heterocycle orheterocycle multiple condensed ring system including a carbon atom and aheteroatom (e.g., a nitrogen). Exemplary heterocycles include, but arenot limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl and 1,4-benzodioxanyl.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7carbon atoms (i.e. (C₃-C₇)carbocycle). The term “carbocycle” or“carbocyclyl” also includes multiple condensed, saturated and partiallyunsaturated all carbon ring systems (e.g., ring systems comprising 2, 3or 4 carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving about 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 carbon atoms). The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Forexample, multicyclic carbocyles can be connected to each other via asingle carbon atom to form a spiro connection (e.g., spiropentane,spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fusedconnection (e.g., carbocycles such as decahydronaphthalene, norsabinane,norcarane) or via two non-adjacent carbon atoms to form a bridgedconnection (e.g., norbornane, bicyclo[2.2.2]octane, etc). The“carbocycle” or “carbocyclyl” can also be optionally substituted withone or more (e.g., 1, 2 or 3) oxo groups. Non-limiting examples ofmonocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

One skilled in the art will recognize that substituents and othermoieties of the compounds of formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of formula Iwhich have such stability are contemplated as falling within the scopeof the present invention.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity). The word “about” may also be representedsymbolically by “˜” in the context of a chemical measurement (e.g.,˜50mg or pH˜7).

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereoisomers

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axesof chirality and whose molecules are not mirror images of one another.Diastereomers typically have different physical properties, e.g.,melting points, boiling points, spectral properties, and reactivities.Mixtures of diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The compounds disclosed herein may have chiral centers, e.g., chiralcarbon atoms. Such compounds thus include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers.In addition, the compounds disclosed herein include enriched or resolvedoptical isomers at any or all asymmetric, chiral atoms. Suchcompositions thus include racemic mixtures of all stereoisomers,including enantiomers, diastereomers, and atropisomers. In addition, thecompositions disclosed herein include enriched or resolved opticalisomers at any or all asymmetric, chiral atoms. In other words, thechiral centers apparent from the depictions are provided as the chiralisomers or racemic mixtures. Both racemic and diastereomeric mixtures,as well as the individual optical isomers isolated or synthesized,substantially free of their enantiomeric or diastereomeric partners, areall within the scope of the invention. The racemic mixtures can beseparated into their individual, substantially optically pure isomersthrough well-known techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.The desired optical isomer can also be synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

It is to be understood that for compounds disclosed herein when a bondis drawn in a non-stereochemical manner (e.g., flat) the atom to whichthe bond is attached includes all stereochemical possibilities. It isalso to be understood that when a bond is drawn in a stereochemicalmanner (e.g., bold, bold-wedge, dashed or dashed-wedge) the atom towhich the stereochemical bond is attached has the stereochemistry asshown unless otherwise noted. Accordingly, in one embodiment, a compounddisclosed herein is greater than 50% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 80% a singleenantiomer. In another embodiment, a compound disclosed herein is atleast 90% a single enantiomer. In another embodiment, a compounddisclosed herein is at least 98% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 99% a singleenantiomer. In another embodiment, a compound disclosed herein isgreater than 50% a single diastereomer. In another embodiment, acompound disclosed herein is at least 80% a single diastereomer. Inanother embodiment, a compound disclosed herein is at least 90% a singlediastereomer. In another embodiment, a compound disclosed herein is atleast 98% a single diastereomer. In another embodiment, a compounddisclosed herein is at least 99% a single diastereomer.

Accordingly, in one embodiment, a composition disclosed herein isgreater than 50% a single enantiomer. In another embodiment, acomposition disclosed herein is at least 80% a single enantiomer. Inanother embodiment, a composition disclosed herein is at least 90% asingle enantiomer. In another embodiment, a composition disclosed hereinis at least 98% a single enantiomer. In another embodiment, acomposition disclosed herein is at least 99% a single enantiomer. Inanother embodiment, a composition disclosed herein is greater than 50% asingle diastereomer. In another embodiment, a composition disclosedherein is at least 80% a single diastereomer. In another embodiment, acomposition disclosed herein is at least 90% a single diastereomer. Inanother embodiment, a composition disclosed herein is at least 98% asingle diastereomer. In another embodiment, a composition disclosedherein is at least 99% a single diastereomer.

Tautomers

The compounds disclosed herein can also exist as tautomeric isomers incertain cases.

Although only one delocalized resonance structure may be depicted, allsuch forms are contemplated within the scope of the invention. Forexample, ene-amine tautomers can exist for purine, pyrimidine,imidazole, guanidine, amidine, and tetrazole systems and all theirpossible tautomeric forms are within the scope of the invention.

Protecting Groups

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Salts and Hydrates

Examples of pharmaceutically acceptable salts of the compounds disclosedherein include salts derived from an appropriate base, such as an alkalimetal (for example, sodium), an alkaline earth metal (for example,magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein each Xis independently selected from H or a C₁-C₄ alkyl group).

A pharmaceutically acceptable salt can refer to a salt of a compoundthat is pharmaceutically acceptable and that possesses (or can beconverted to a form that possesses) the desired pharmacological activityof the parent compound. Examples of pharmaceutically acceptable salts ofthe compounds disclosed herein include salts derived from an appropriatebase, such as an alkali metal (for example, sodium), an alkaline earthmetal (for example, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an aminogroup include for example salts of organic carboxylic acids such asacetic, benzoic, camphorsulfonic, citric, glucoheptonic, gluconic,lactic, fumaric, tartaric, maleic, malonic, malic, mandelic, isethionic,lactobionic, succinic, 2-napththalenesulfonic, oleic, palmitic,propionic, stearic, and trimethylacetic acids; organic sulfonic acids,such as methanesulfonic, ethanesulfonic, benzenesulfonic andp-toluenesulfonic acids; and inorganic acids, such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids.Pharmaceutically acceptable salts of a compound of a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group). Pharmaceutically acceptable salts also include saltsformed when an acidic proton present in the parent compound is replacedby either a metal ion, e.g., an alkali metal ion, an alkaline earth ion,or an aluminum ion; or coordinates with an organic base such asdiethanolamine, triethanolamine, N-methylglucamine and the like. Alsoincluded in this definition are ammonium and substituted or quaternizedammonium salts. Representative non-limiting lists of pharmaceuticallyacceptable salts can be found in S. M. Berge et al., J. Pharma Sci.,66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy,R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins,Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which arehereby incorporated by reference herein.

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of formula I or another compound disclosedherein. All salts, whether or not derived from a physiologicallyacceptable acid or base, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound disclosed herein. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, such as amines. Finally, it is to be understoodthat the compositions herein comprise compounds disclosed herein intheir un-ionized, as well as zwitterionic form, and combinations withstoichiometric amounts of water as in hydrates.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

Isotopes

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,a —CH₃ group may be substituted with —CD₃.

Specific values listed below for radicals, substituents, and ranges arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

Compounds of Formula I

A specific group of compounds of formula I are compounds of formula Ia:

or a salt thereof. In certain embodiments, a salt is a pharmaceuticallyacceptable salt.

A specific group of compounds of formula I are compounds of formula Ib:

or a salt thereof. In certain embodiments, a salt is a pharmaceuticallyacceptable salt.

A specific value for A is selected from imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,oxazolyl and isoxazolyl, wherein imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,oxazolyl and isoxazolyl are each substituted with one Z¹ group andoptionally substituted with one or more (e.g., 1, 2 or 3) Z² groups.

A specific value for A is selected from imidazol-2-yl,1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, thiazol-4-yl, thiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, oxazol-5-yl, isoxazol-3-yl,imidazol-4-yl and oxazol-4-yl, wherein imidazol-2-yl,1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, thiazol-4-yl, thiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, oxazol-5-yl, isoxazol-3-yl,imidazol-4-yl and oxazol-4-yl are each substituted with one Z¹ group andoptionally substituted with one or more (e.g., 1, 2 or 3) Z² groups.

A specific value for A is selected from imidazolyl, 1,2,4-triazolyl,thiazolyl, 1,2,4-oxadiazolyl and isoxazolyl, wherein imidazolyl,1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl and isoxazolyl are eachsubstituted with one Z¹ group and optionally substituted with one ormore (e.g., 1, 2 or 3) Z² groups.

A specific value for A is selected from imidazol-2-yl,1,2,4-triazol-3-yl, thiazol-4-yl, 1,2,4-oxadiazol-5-yl, isoxazol-3-yland imidazol-4-yl, wherein imidazol-2-yl, 1,2,4-triazol-3-yl,thiazol-4-yl, 1,2,4-oxadiazol-5-yl, isoxazol-3-yl and imidazol-4-yl areeach substituted with one Z¹ group and optionally substituted with oneor more (e.g., 1, 2 or 3) Z² groups.

A specific value for the 5-membered N-heteroaryl A is:

wherein the dashed bond is a single or double bond so that ring A isaromatic, and A is substituted with one Z¹ group and optionallysubstituted with one or more (e.g., 1, 2 or 3) Z² groups.

A specific value for the 5-membered N-heteroaryl A is:

wherein the dashed bonds are single or double bonds so that ring A isaromatic, X is N or C, and A is optionally substituted with one or more(e.g., 1, 2 or 3) Z² groups.

A specific value for the 5-membered N-heteroaryl A is:

wherein X is N or C, each X¹ is independently selected from N, NZ^(2a),O, S and CZ^(2a), the dashed bonds are selected from single and doublebonds so that ring A is aromatic, and Z^(2a) is selected from H and Z².

A specific value for the 5-membered N-heteroaryl A is:

wherein X is N or C, each X¹ is independently selected from N, NZ^(2a),O, S and CZ^(2a), the dashed bonds are selected from single and doublebonds so that ring A is aromatic, and Z^(2a) is selected from H and Z²;provided that at least one X¹ group is other than O or S.

A specific value for A is selected from:

wherein each Z^(2a) is independently selected from Z² and H.

A specific value for A is selected from

wherein each Z^(2a) is independently selected from Z² and H.

A specific value for each Z¹ is independently selected from(C₃-C₈)alkyl, aryl, heteroaryl and aryl(C₁-C₆)alkyl-, wherein any aryl,heteroaryl and aryl(C₁-C₆)alkyl of Z¹ is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b) groups, and wherein any(C₃-C₅)alkyl of Z¹ is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z^(1a) groups.

A specific value for each Z¹ is independently selected from(C₃-C₈)alkyl, aryl and aryl(C₁-C₆)alkyl-, wherein any aryl andaryl(C₁-C₆)alkyl- of Z¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b) groups, and wherein any(C₃-C₈)alkyl of Z¹ is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z^(1a) groups.

A specific value for Z¹ is independently selected from phenyl andbenzyl, wherein any phenyl and benzyl of Z¹ is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b) groups.

A specific value for each Z^(1a) is independently selected from halogenand —OR_(n1).

A specific value for Z^(1b) is (C₁-C₆)alkyl.

A specific group of compounds of formula I are compounds wherein eachZ^(1a) is independently selected from halogen and —OR_(n1) and eachZ^(1b) is (C₁-C₆)alkyl.

A specific group of compounds of formula I are compounds wherein eachZ^(1a) is independently selected from halogen and —OR_(n1), Z^(1b) is(C₁-C₆)alkyl, and wherein R_(1n) is (C₁-C₆)alkyl.

A specific value for R_(n1) is (C₁-C₆)alkyl.

A specific value for R_(n1) is methyl.

A specific value for each Z^(1a) is independently selected from chloroand methoxy and each Z^(1b) is methyl.

A specific value for each Z² is independently selected from(C₁-C₃)alkyl.

A specific value for Z² is methyl.

A specific value for A is selected from

A specific value for A is selected from

A specific value for R² is phenyl or a 5-membered heteroaryl, whereinany phenyl or 5-membered heteroaryl is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for R² is phenyl optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for each Z⁴ is halogen.

A specific value for Z⁴ is fluoro.

A specific value for R² is 3,5-difluorophenyl.

A specific value for R¹ is bicyclic-heteroaryl, wherein anybicyclic-heteroaryl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is a bicyclic-heteroaryl ortricyclic-heteroaryl, wherein any bicyclic-heteroaryl ortricyclic-heteroaryl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein one ring of thebicyclic-heteroaryl is a partially unsaturated ring, and wherein thebicyclic-heteroaryl is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl or tricyclic-heteroaryl,wherein one ring of the bicyclic-heteroaryl or tricyclic-heteroaryl is apartially unsaturated ring, and wherein the bicyclic-heteroaryl ortricyclic-heteroaryl is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl is a 5-membered ring fused to a 6-membered ring,wherein the 5-membered ring fused to a 6-membered ring is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl is a 5-membered aromatic ring fused to a 6-memberedring, wherein the 5-membered ring fused to a 6-membered ring isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 4 to 12 carbon atoms and 1-5 heteroatoms withinthe bicyclic-heteroaryl ring system, and wherein the bicyclic-heteroarylis optionally substituted with one or more Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl or tricyclic-heteroaryl,wherein the bicyclic-heteroaryl or tricyclic-heteroaryl has 4 to 12carbon atoms and 1-5 heteroatoms within the bicyclic-heteroaryl ortricyclic-heteroaryl ring, and wherein the bicyclic-heteroaryl ortricyclic-heteroaryl is optionally substituted with one or more Z³groups.

A specific value for R¹ is a bicyclic-heteroaryl ortricyclic-heteroaryl, wherein the bicyclic-heteroaryl ortricyclic-heteroaryl has 4-9 carbon atoms and 1-5 heteroatoms in thering system, and wherein any bicyclic-heteroaryl or tricyclic-heteroarylof R¹ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z⁴ groups.

A specific value for R¹ is a bicyclic-heteroaryl ortricyclic-heteroaryl, wherein the bicyclic-heteroaryl ortricyclic-heteroaryl has 6-9 carbon atoms and 1-3 heteroatoms in thering system, and wherein any bicyclic-heteroaryl or tricyclic-heteroarylof R¹ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 4 to 10 carbon atoms and 1-5 heteroatoms withinthe bicyclic-heteroaryl ring system, and wherein the bicyclic-heteroarylis optionally substituted with one or more Z³ groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 6 to 9 carbon atoms and 1-4 heteroatoms withinthe bicyclic-heteroaryl ring system, and wherein the bicyclic-heteroarylis optionally substituted with one or more Z³ groups.

A specific value for R¹ is selected from indolyl,4,5,6,7-tetrahydro-indazolyl, benzo[d]imidazolyl andpyrrolo[3,2-b]pyridinyl, wherein any indolyl,4,5,6,7-tetrahydro-indazole, benzo[d]imidazolyl andpyrrolo[3,2-b]pyridinyl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is selected from indolyl,4,5,6,7-tetrahydro-indazolyl, benzo[d]imidazolyl,pyrrolo[3,2-b]pyridinyl,3b,4,4a,5-tetrahydro-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole wherein any indolyl,4,5,6,7-tetrahydro-indazolyl, benzo[d]imidazolyl,pyrrolo[3,2-b]pyridinyl,3b,4,4a,5-tetrahydro-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole of R¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is selected from indol-3-yl,4,5,6,7-tetrahydro-1H-indazol-1yl, benzo[d]imidazol-1-yl and1H-pyrrolo[3,2-b]pyridin-3-yl, wherein any indol-3-yl,4,5,6,7-tetrahydro-1H-indazol-1yl, benzo[d]imidazole-1-yl and1H-pyrrolo[3,2-b]pyridine-3-yl of R¹ is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for R¹ is selected from indol-3-yl,4,5,6,7-tetrahydro-1H-indazol-1yl, benzo[d]imidazol-1-yl,1H-pyrrolo[3,2-b]pyridin-3-yl, 4,5,6,7-tetrahydro-1H-indazol-1-yl,3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazol-1-yl wherein any indol-3-yl,4,5,6,7-tetrahydro-1H-indazol-1yl, benzo[d]imidazol-1-yl,1H-pyrrolo[3,2-b]pyridin-3-yl, 4,5,6,7-tetrahydro-1H-indazol-1-yl,3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazol-1-yl of R¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³ groups.

A specific value for each Z³ is independently selected from(C₁-C₆)alkyl, halogen and OR_(n2), wherein any (C₁-C₆)alkyl of Z³ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) halogen.

A specific value for each Z³ is independently selected from(C₁-C₆)alkyl, halogen, —CN and OR_(n2), wherein any (C₁-C₆)alkyl of Z³is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)halogen.

A specific group of compounds of formula I are compounds wherein each Z³is independently selected from (C₁-C₆)alkyl, halogen and OR_(n), whereinany (C₁-C₆)alkyl of Z³ is optionally substituted with one or morehalogen and wherein R_(n2) is hydrogen or (C₁-C₆)alkyl.

A specific group of compounds of formula I are compounds wherein each Z³is independently selected from (C₁-C₆)alkyl, halogen, —CN and OR_(n),wherein any (C₁-C₆)alkyl of Z³ is optionally substituted with one ormore halogen and wherein R_(n2) is hydrogen or (C₁-C₆)alkyl.

A specific value for R_(n2) is hydrogen or (C₁-C₆)alkyl.

A specific value for R_(n2) is hydrogen or methyl.

A specific value for each Z³ is independently selected from fluoro,hydroxy, trifluoromethyl, methyl and methoxy.

A specific value for each Z³ is independently selected from fluoro,hydroxy, trifluoromethyl, methyl, —CN and methoxy.

A specific value for R¹ is selected from:

A specific value for R¹ is selected from:

A specific value for R¹ is selected from:

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 2 to 14 carbon atoms and 1-5 heteroatoms withinthe bicyclic-heteroaryl ring system, wherein the bicyclic-heteroaryl isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 4 to 12 carbon atoms and 1-5 heteroatoms withinthe bicyclic-heteroaryl ring system, wherein the bicyclic-heteroaryl isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 4 to 10 carbon atoms and 1-5 heteroatoms withinthe bicyclic-heteroaryl ring system, wherein the bicyclic-heteroaryl isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³groups.

A specific value for R¹ is bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 4 to 8 carbon atoms and 1-5 heteroatoms withinthe bicyclic-heteroaryl ring system, wherein the bicyclic-heteroaryl isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z³groups.

A specific value for R¹ is a value for R¹ as depicted in any or all ofthe examples as described herein below.

A specific value for R² is a value for R² as depicted in any or all ofthe examples as described herein below.

A specific value for A is a value for A as depicted in any or all of theexamples as described herein below.

One embodiment provides a compound of formula I as described in any orall of the examples as described herein below.

One embodiment provides an isomer (e.g., stereoisomer such as anenantiomer or diastereomer) of a compound of formula I as described inany or all of the examples as described herein below.

One embodiment provides a racemic mixture of a compound of formula I asdescribed in any or all of the examples as described herein below.

In one embodiment a heteroaryl is a monocyclic-heteroaryl,bicyclic-heteroaryl or tricyclic-heteroaryl.

In one embodiment a heteroaryl is a bicyclic-heteroaryl ortricyclic-heteroaryl.

In one embodiment a heteroaryl is a monocyclic-heteroaryl orbicyclic-heteroaryl.

In one embodiment a heteroaryl is a monocyclic-heteroaryl.

In one embodiment a heteroaryl is a bicyclic-heteroaryl.

In one embodiment a heteroaryl is a tricyclic-heteroaryl.

In one embodiment a heterocycle is a monocyclic-heterocycle,bicyclic-heterocycle or tricyclic-heterocycle.

In one embodiment a heterocycle is a bicyclic-heterocycle ortricyclic-heterocycle.

In one embodiment a heterocycle is a monocyclic-heterocycle orbicyclic-heterocycle.

In one embodiment a heterocycle is a monocyclic-heterocycle.

In one embodiment a heteroaryl is a bicyclic-heterocycle.

In one embodiment a heteroaryl is a tricyclic-heterocycle.

In one embodiment a heteroaryl has 1 to 14 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heteroaryl has 1 to 12 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heteroaryl has 1 to 10 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heteroaryl has 1 to 8 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heteroaryl has 1 to 6 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heterocycle has 2 to 14 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heterocycle includes 2 to 12 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heterocycle includes 2 to 10 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heterocycle includes 2 to 8 carbon atoms and 1-5heteroatoms within the ring system.

In one embodiment a heterocycle includes 2 to 6 carbon atoms and 1-5heteroatoms within the ring system.

One embodiment provides a compound selected from:

and salts thereof.

One embodiment provides a compound selected from:

and salts thereof.

General Synthetic Procedures

Schemes 1, 2 and 3 describe methods that can be used to preparecompounds of formula I.

Scheme 1 describes a general synthetic route which can be used toprepare compounds of formula I. An appropriately substituted heteroarylnitrile may be reacted with a Grignard reagent followed by reduction toprovide compounds of formula A2. The amine can be coupled to a varietyof carboxcyclic acid derivatives to provide compounds of formula A3.

Scheme 2 describes a general stereoselective route which can be used toprepare compounds of formula I. Heteroaryl aldehydes of formula B1 canbe condensed with a chiral auxiliary to provide a stereoselectiveaddition of a nucleophilic reagent. Depicted in Scheme 2 is thecondensation of an appropriately substituted heterocyclic aldehyde B1with tert-butane sulfinamide and the addition of a Grignard reagent toprovide a mixture of B3 and B4 enriched in B3. This mixture may beseparated by column chromatography on silica gel to provide purediastereomers. Removal of the auxiliary provides amines B5 and B6 whichcan be coupled to a variety of carboxylic acids to provide compounds offormula B7 and B8.

Scheme 3 describes a general stereoselective route which can be used toprepare compounds of formula I. Heteroaryl aldehydes of formula B1 canbe condensed with a chiral auxiliary to provide a stereoselectiveaddition of a nucleophilic reagent. Depicted in Scheme 3 is thecondensation of an bromo-substituted heterocyclic aldehyde C1 with (S)tert-butane sulfinamide and the addition of a Grignard reagent toprovide a mixture of C3 and C4 enriched in C3. This mixture may beseparated by column chromatography on silica gel to provide purediastereomers. Removal of the auxiliary provides amines C5 and C6 whichcan be coupled to a variety of carboxylic acids to provide heteroarylcompounds of formula C7 and C8. Diversification of C7 and C8 may beaccomplished by a variety of methods including metal catalyzed crosscoupling reactions such as Suzuki couplings and Sonogashira couplings.

Combination Therapy

In one embodiment, the invention provides a method for treating an HIVinfection, comprising administering to a patient in need thereof atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents which are suitable for treating an HIV infection.

In one embodiment, a method for treating or preventing an HIV infectionin a human having or at risk of having the infection is provided,comprising administering to the human a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents.

In one embodiment, the invention provides pharmaceutical compositionscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with at least one additional therapeuticagent, and a pharmaceutically acceptable carrier. For example, thetherapeutic agent used in combination with the compound disclosed hereincan be any anti-HIV agent.

In one embodiment, combination pharmaceutical agents comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with one or more additional therapeutic agentsare provided.

One embodiment provides pharmaceutical compositions comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with at least one additional therapeutic agent,and a pharmaceutically acceptable carrier. In one embodiment, theadditional therapeutic agent may be an anti-HIV agent. For example, insome embodiments, the additional therapeutic agent is selected from thegroup consisting of HIV protease inhibiting compounds (HIV proteaseinhibitors), HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, HIVnon-catalytic site (or allosteric) integrase inhibitors, entryinhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusioninhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerizationinhibitors or capsid disrupting compounds such as those disclosed in US2013/0165489 (University of Pennsylvania), and WO 2013/006792 (PharmaResources), pharmacokinetic enhancers, and other drug for treating HIV,and combinations thereof.

In further embodiments, the additional therapeutic agent is selectedfrom one or more of:

(1) HIV protease inhibitors selected from the group consisting ofamprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir,nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase selected from the group consisting of capravirine,emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A,etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120,rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806,KM023 and MK-1439;

(3) HIV nucleoside inhibitors of reverse transcriptase selected from thegroup consisting of zidovudine, emtricitabine, didanosine, stavudine,zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine,MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil,apricitibine (AVX754), amdoxovir, KP-1461, GS-9131 (Gilead Sciences) andfosalvudine tidoxil (formerly HDP 99.0003);

(4) HIV nucleotide inhibitors of reverse transcriptase selected from thegroup consisting of tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide fumarate (Gilead Sciences), tenofovir alafenamide (GileadSciences), GS-7340 (Gilead Sciences), GS-9148 (Gilead Sciences),adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);

(5) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, andL-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011, elvitegravir, dolutegravir and GSK-744;

(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI)including, but not limited to, BI-224436, CX0516, CX05045, CX14442,compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO2012/003498 (Gilead Sciences) each of which is incorporated by referencein its entirety herein;

(7) gp41 inhibitors selected from the group consisting of enfuvirtide,sifuvirtide, albuvirtide, FB006M, and TRI-1144;

(8) the CXCR4 inhibitor AMD-070;

(9) the entry inhibitor SP01A;

(10) the gp120 inhibitor BMS-488043;

(11) the G6PD and NADH-oxidase inhibitor immunitin;

(12) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798(Pfizer), and CCR5mAb004;

(13) CD4 attachment inhibitors selected from the group consisting ofibalizumab (TMB-355) and BMS-068 (BMS-663068);

(14) pharmacokinetic enhancers selected from the group consisting ofcobicistat and SPI-452; and

(15) other drugs for treating HIV selected from the group consisting ofBAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1,PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, andPA-1050040 (PA-040).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with two, three,four or more additional therapeutic agents. In certain embodiments, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with two additional therapeutic agents. In otherembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with three additional therapeuticagents. In further embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with fouradditional therapeutic agents. The two, three four or more additionaltherapeutic agents can be different therapeutic agents selected from thesame class of therapeutic agents, or they can be selected from differentclasses of therapeutic agents. In a specific embodiment, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with an HIV nucleotide inhibitor of reverse transcriptase andan HIV non-nucleoside inhibitor of reverse transcriptase. In anotherspecific embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleotide inhibitor ofreverse transcriptase, and an HIV protease inhibiting compound. In afurther embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleotide inhibitor ofreverse transcriptase, an HIV non-nucleoside inhibitor of reversetranscriptase, and an HIV protease inhibiting compound. In an additionalembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleotide inhibitor ofreverse transcriptase, an HIV non-nucleoside inhibitor of reversetranscriptase, and a pharmacokinetic enhancer.

In some embodiments, one or more of the compounds disclosed herein arecombined with one or more other active therapeutic agents in a unitarydosage form for simultaneous or sequential administration to a patient.The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

In some embodiments, one or more of the compounds disclosed herein areco-administered with one or more other active therapeutic agents.Co-administration of a compound disclosed herein with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound disclosed herein and one or more otheractive therapeutic agents, such that therapeutically effective amountsof disclosed herein and one or more other active therapeutic agents areboth present in the body of the patient.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents such as those disclosed above.

Pharmaceutical Formulations

The compounds disclosed herein are formulated with conventional carriers(e.g., inactive ingredient or excipient material) which will be selectedin accord with ordinary practice. Tablets will contain excipientsincluding glidants, fillers, binders and the like. Aqueous formulationsare prepared in sterile form, and when intended for delivery by otherthan oral administration generally will be isotonic. All formulationswill optionally contain excipients such as those set forth in theHandbook of Pharmaceutical Excipients (1986). Excipients includeascorbic acid and other antioxidants, chelating agents such as EDTA,carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. One embodimentprovides the formulation as a solid dosage form including a solid oraldosage form. The pH of the formulations ranges from about 3 to about 11,but is ordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers and optionallyother therapeutic ingredients. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipients, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units including but not limited tocapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient.

Pharmaceutical formulations according to the present invention compriseone or more compounds disclosed herein together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In certain embodiments, the carriermaterial varies from about 5 to about 95% of the total compositions(weight:weight).

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds disclosed herein (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds disclosed herein is that they are orally bioavailableand can be dosed orally.

The antiviral properties of a compound disclosed herein may bedetermined using Test A described below.

Test A: Antiviral Assay in MT4 Cells

For the antiviral assay, 40 μL of 1× test concentration of 3-foldserially diluted compound in culture medium with 10% FBS was added toeach well of a 384-well plate (10 concentrations) in quadruplicate. MT-4cells were next mixed with HIV-IIIb at an m.o.i of 0.003 for 1 hour,after which time 35 μL of virus/cell mixture (2000 cells) wasimmediately added to each well containing 40 μL of diluted compound. Theplates were then incubated at 37° C. for 5 days. After 5 days ofincubation, 25 μl of 2× concentrated CellTiter-Glo™ Reagent (catalog#G7571, Promega Biosciences, Inc., Madison, Wis.) was added to each wellcontaining MT-4 cells. Cell lysis was carried out by incubating at roomtemperature for 10 min and then chemiluminescence was read. EC50 valueswere defined as the compound concentration that caused a 50% decrease inluminescence signal, a measure of HIV-1 replication. Percent inhibitionof virus-induced cell killing calculated from the dose response curve at4 μM drug concentration is shown in the table below.

Test B:Cytotoxicity assay

Compound cytotoxicity and the corresponding CC50 values was determinedusing the same protocol as described in the antiviral assay (Test A)except that uninfected cells were used.

Compounds disclosed herein demonstrate antiviral activity (Test A) asdepicted in the table below. Accordingly, the compounds disclosed hereinmay be useful for treating an HIV virus infection, treating AIDS or fordelaying the onset of AIDS or ARC symptoms. Shown below are thecorresponding values for CC50 and percent inhibition of virus-inducedcell killing in the presence of 6 μM drug concentration.

Compound % inhibition at 6 μM CC50 (nM) 1E 83 21864 2 6 27782 3C 1937057 4 64 11373 5F 79 13456 6B 4 11952 7 121 >47114 8 6 44341 9E 013198 10G 51 >53192 11 76 >53000 12 4 >53000 13E 93 25405 14 60 1130615C 0 34996 16 0 51909 17B 0 >53000 18B 4 >53000 19F 0 9141 20 1 1223321 2 25394 22 1 50712 23 0 12045 24 5 13637 25I 68 9894 26 106 19525 2728 6166 28B 3 11629 29G 44 10776 30 69 11014 31 75 25410 32 0 11872 33H3 31802 34 0 22136 35 0 15311 36 0 16283 37 0 10214 38 0 19143

In one embodiment, the compounds demonstrate >10% inhibition at 6 μM. Inone embodiment, the compounds demonstrate >30% inhibition at 6 μM. Inone embodiment, the compounds demonstrate >50% inhibition at 6 μM. Inone embodiment, the compounds demonstrate >70% inhibition at 6 μM. It isto be understood that the compounds disclosed herein can be groupedaccording to their % inhibition as described above.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

Example 1

Synthesis of (S)-tert-butyl 1-(1H-imidazol-2-yl)-2-phenylethylcarbamate(1B)

To (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (2 g, 8.02mmol) and glyoxal trimeric dehydrate (880 mg, 4.19 mmol) in MeOH (12 mL)was added 2N NH₃ in MeOH (18.3 mL). The reaction was stirred at ambienttemperature for 15 hr. Solvents were evaporated in vacuo and the residuepartitioned between EtOAc and aqueous saturated NaCl. The organics wereseparated, dried, and removed in vacuo to provide the title compound: MS(m/z) 288.1 [M+H]⁺.

Synthesis of (S)-1-(1H-imidazol-2-yl)-2-phenylethanamine (1C)

(S)-tert-Butyl 1-(1H-imidazol-2-yl)-2-phenylethylcarbamate (355 mg, 1.18mmol) was dissolved in DCM (5 mL) and treated with 4N HCl in dioxanes(12 mL). After 3 hr, solvents were removed in vacuo and the crudeproduct was used directly in the next reaction.

Synthesis of(S)—N-(1-(1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(1D)

To (S)-1-(1H-imidazol-2-yl)-2-phenylethanamine from the previousreaction was added DMF (10 mL),2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(288 mg, 1.18 mmol), and HATU (530 mg, 1.4 mmol). Diisopropylethylamine(452 μL, 2.6 mmol) was added and the reaction was stirred for 15 min.The reaction was partitioned between EtOAc and H₂O. The organics wereseparated, washed with saturated aqueous NaHCO₃, and saturated aqueousNaCl. Solvents were removed in vacuo and the residue purified by columnchromatography on silica to provide the desired product: MS (m/z) 418.3[M+H]⁺.

Synthesis of(S)—N-(2-phenyl-1-(1-phenyl-1H-imidazol-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(1E)

To(S)—N-(1-(1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(111 mg, 0.27 mmol) in NMP (0.6 mL) was added iodobenzene (27 L, 0.24mmol), Cu₂O (1 mg), PEG 3500 (50 mg), 4,7-dimethoxy-1,10-phenanthroline(6 mg) and Cs₂CO₃ (110 mg, 0.34 mmol). The reaction was heated to 115°C. for 4 hr. After cooling to ambient temperature, the reaction mixturewas filtered over a heavy metal scavenging column and eluted with DCM.The solvents were removed in vacuo and the residue purified by RP HPLCto provide the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s),7.55 (s, 1H), 7.42 (t, 1H), 7.14 (q, 2H), 7.01 (d, 1H), 6.84 (dd, 1H),4.77-4.71 (m, 1H), 3.08 (d, 1H), 2.36 (s, 1H), 1.62 (d, 2H). MS (m/z)494.3 [M+H]⁺.

Example 2

Synthesis of(S)—N-(1-(1-isopentyl-1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(2)

(S)—N-(1-(1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(42 mg, 0.1 mmol) and 1-bromo-3-methylbutane (24 μL, 0.2 mmol) werecombined in DMF (0.6 mL) and treated with K₂CO₃ (21 mg, 0.15 mmol) andTBAI (4 mg). The reaction was heated to 90° C. and stirred for 15 h. Thereaction was purified by RP HPLC to provide the title compound: ¹H NMR(400 MHz, DMSO-d₆) δ 7.23 (q, 7.5 Hz, 3H), 7.16-7.09 (m, 2H), 5.24 (m,1H), 4.75 (s, 2H), 3.83 (m, 3H), 3.22 (d, 1H), 2.35 (m, 2H), 1.63 (m,5H), 1.40 (m, 2H), 0.77 (t, 6H). MS (m/z) 488.5 [M+H]⁺.

Example 3

Synthesis of (S)-tert-butyl1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethylcarbamate (3A)

To (S)-tert-butyl 1-(1H-imidazol-2-yl)-2-phenylethylcarbamate (120 mg,0.42 mmol) in DMF (1 mL) was added 1-(bromomethyl)-2-methoxybenzene (58μL, 0.42 mmol), K₂CO₃ (70 mg, 0.5 mmol) and TBAI (5 mg) and heated to90° C. After stirring for 1 hr and cooling to ambient temperature, thereaction was partitioned between EtOAc and H₂O. The organics wereseparated, washed with saturated aqueous NaHCO₃, and saturated aqueousNaCl. Solvents were removed in vacuo and the residue purified by columnchromatography on silica to provide the desired product: MS (m/z) 408.2[M+H]⁺.

Synthesis of(S)-1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine (3B)

(S)-tert-butyl1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethylcarbamate wasdissolved in DCM and treated with 4 N HCl in dioxanes. The reaction wasstirred for 3 hr. Solvents were removed in vacuo to provide the desiredproduct. MS (m/z) 308.1 [M+H]⁺.

Synthesis of(S)-2-(5-hydroxy-1H-indol-3-yl)-N-(1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethyl)acetamide(3C)

(S)-1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine (75 mg,0.2 mmol), 2-(5-hydroxy-1H-indol-3-yl)acetic acid (47 mg, 0.25 mmol) andHATU (97 mg, 0.26 mmol) were combined in DMF (2 mL) and treated withdiisopropylethylamine (70 μL). The reaction was stirred for 30 min andthe purified by RP HPLC to provide the title compound: ¹H NMR (400 MHz,DMSO-d₆) δ 10.53 (d, 1H), 8.67 (d, 1H), 7.58 (s, 1H), 7.38-7.28 (m, 2H),7.20-7.12 (m, 3H), 7.12-6.98 (m, 4H), 6.91-6.79 (m, 3H), 6.72 (d, 1H),6.57 (dd, 1H), 5.38-5.31 (m, 1H), 5.17 (d, 2H), 3.71 (s, 3H), 3.40-3.22(m, 3H), 3.16 (dd, 1H). MS (m/z) 481.2 [M+H]⁺.

Example 4

Synthesis of(S)-2-(5-hydroxy-1H-indol-3-yl)-N-(1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethyl)acetamide(4)

The title compound was prepared according to the method presented in thesynthesis of Example 3 utilizing 3B and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid.¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 7.33 (t, 2H), 7.21 (d, 4H),7.11 (d, 3H), 7.02 (d, 1H), 6.87 (t, 2H), 5.40 (s, 1H), 5.16 (s, 2H),4.62 (q, 3H), 3.72 (s, 3H), 3.29-3.19 (m, 3H), 2.18 (d, 1H), 1.62 (t,4H). MS (m/z) 538.5 [M+H]⁺.

Example 5

Synthesis of(R)—N-((1-(4-methoxyphenyl)-1H-imidazol-2-yl)methylene)-2-methylpropane-2-sulfinamide(5B)

1-(4-methoxyphenyl)-1H-imidazole-2-carbaldehyde (200 mg, 1 mmol),(R)-2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol), and CuSO₄ (160 mg,1 mmol) were combined in DCM (5 mL). The reaction was stirred at ambienttemperature for 15 hr. The reaction was filtered, solvents removed invacuo, and the residue purified by column chromatography on silica toprovide the desired product: MS (m/z) 305.9 [M+H]⁺.

Synthesis of(R)—N—((R)-2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamideand(R)—N—((S)-2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide(5C and 5D)

(R)—N-((1-(4-methoxyphenyl)-1H-imidazol-2-yl)methylene)-2-methylpropane-2-sulfinamide(130 mg, 0.43 mmol) was dissolved in THF (2 mL) and cooled to −78° C.(3,5-difluorobenzyl)magnesium bromide (2 mL of a 0.25 solution indiethylether) was added dropwise. The reaction was stirred at −78° C.for 2 hr then let warm to −40° C. and quenched with H₂O. The reactionsolution was extracted with EtOAc. The organics were separated, washedwith saturated aqueous NaHCO₃, and dried with saturated aqueous NaCl.Solvents were removed in vacuo and the residue purified by columnchromatography on silica to provide 5C (Rf=0.3 EtOAc, MS (m/z) 434.1[M+H]⁺) and 5D (Rf=0.2 EtOAc, MS (m/z) 434.1 [M+H]⁺).

Synthesis of(S)-2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethanamine(5E)

(R)—N—((S)-2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide(40 mg, 0.09 mmol) was dissolved in DCM (0.7 mL) and treated with 4N HClin dioxanes (0.7 mL). The reaction was stirred for 3 hr. Solvents wereremoved in vacuo and the crude product was used directly in the nextstep. MS (m/z) 330.1 [M+H]⁺.

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(5F)

The title compound as prepared according to the method presented in thesynthesis of Example 1 utilizing 5E. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03(s, 1H), 7.10 (d, 2H), 6.99 (t, 3H), 6.63 (d, 2H), 5.01 (d, 1H), 4.68(s, 2H), 3.76 (s, 3H), 3.11 (d, 2H), 2.34 (s, 1H), 1.63 (s, 4H); MS(m/z) 560.4 [M+H]⁺.

Example 6

Synthesis of(R)-2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethanamine(6A)

The title compound as prepared according to the method presented in thesynthesis of Example 5 utilizing 5C. MS (m/z) 330.1 [M+H]⁺.

Synthesis of(R)—N-(2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(6B)

The title compound as prepared according to the method presented in thesynthesis of Example 1 utilizing 6A. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08(s, 1H), 7.53 (s, 1H), 7.16-7.08 (m, 2H), 7.08-6.95 (m, 3H), 6.64 (d,2H), 5.03 (q, 1H), 4.77-4.62 (m, 2H), 3.76 (s, 3H), 3.12 (d, 2H),2.47-2.24 (m, 2H), 1.63 (dq, 4H); MS (m/z) 560.4 [M+H]⁺.

Example 7

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(7)

The title compound as prepared according to the method presented in thesynthesis of Example 5 utilizing 5E and2-(5-hydroxy-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆) δ10.53 (s, 1H), 8.69 (s, 1H), 7.09 (d, 1H), 7.03-6.95 (m, 3H), 6.89 (d,2H), 6.77 (d, 1H), 6.61-6.52 (m, 3H), 4.91 (s, 1H), 3.73 (s, 3H), 3.40(s, 2H); MS (m/z) 503.4 [M+H]⁺.

Example 8

Synthesis of(R)—N-(2-(3,5-difluorophenyl)-1-(1-(4-methoxyphenyl)-1H-imidazol-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(8)

The title compound as prepared according to the method presented in thesynthesis of Example 6 utilizing 6A and2-(5-hydroxy-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆) δ10.53 (s, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 7.54 (s, 1H), 7.13-6.95 (m,5H), 6.90 (d, 2H), 6.77 (d, 1H), 6.61-6.53 (m, 3H), 4.91 (q, 1H), 3.74(s, 3H), 3.51-3.34 (m, 2H), 3.18-3.01 (m, 2H); MS (m/z) 503.4 [M+H]⁺.

Example 9

Synthesis of 1-phenyl-1H-1,2,3-triazole-5-carboxamide (9B)

To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (1.0 g,5.6 mmol) and 4-methylmorpholine (0.57 g, 5.6 mmol) in1,2-dimethoxyethane (5 mL), isobutyl chloroformate (0.77, 5.6 mmol) wasadded to the mixture. After 30 minutes, ammonia in dioxane (16.8 mL, 8.4mmol) was added to the reaction. Then it was stirred overnight. Thesolvent was removed and dissolved in 50 mL of ethyl acetate. The organiclayer was washed with brine twice. The organic layer was dried withNa₂SO₄, filtered and concentrated and used without further purification.MS (m/z) 189 [M+H]⁺.

Synthesis of 1-phenyl-1H-1,2,3-triazole-5-carbonitrile (9C)

To a solution of 9B (crude product) and DIPEA (1.5 mL, 8.4 mmol) indichloromethane (10 mL), methanesulfonic anhydride (1.17, 6.7 mmol) wasadded to the mixture. Then it was stirred for overnight. The organiclayer was washed with brine twice. The organic layer was dried withNa₂SO₄, filtered and concentrated. The crude product was purified byflash column (Rf: 0.6, 15% EtOAc/Hexanes) to provide the desiredproduct. MS (m/z) 171 [M+H]⁺.

Synthesis of 2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-5-yl)ethanamine (9D)

To a solution of 9C (280 mg, 1.63 mmol) in tetrahydrofuran (5 mL),benzylmagnesium chloride (2M in THF) (1.23 mL, 2.46 mmol) was addeddropwise. After 3 hours, 3 mL of 2-butanol was added to the reaction andsodium borohydride (0.5 g) was added to the mixture by portion. Thereaction was monitored by LC/Mass until it was done. Methanol (5 mL) wasadded to the mixture. The organic layer was washed with brine andextracted with ethyl acetate (50 mL twice). The organic layer was driedwith Na₂SO₄, filtered and concentrated. The crude product was purifiedby flash column (Rf: 0.3, 3% MeOH/DCM) to provide the desired product.MS (m/z) 265 [M+H]⁺.

Synthesis ofN-(2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-5-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(9E)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL).After 10 minutes, 9D (26.5 mg, 0.1 mmol) in 0.2 mL of DMF was added tothe reaction. The reaction was stirred for 2 hours. LC/MS shows desiredproduct with a small amount of acid. Purified reaction mixture on prepreverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1%TFA/Acetonitrile). Combined pure fractions as determined by LC/MS andlyophilized to provide the desired compound. ¹H NMR (400 MHz, DMSO) δ9.02 (d, J=7.9 Hz, 1H), 7.96 (s, 1H), 7.58-7.42 (m, 3H), 7.30-7.18 (m,2H), 7.18-7.06 (m, 3H), 7.00-6.86 (m, 2H), 5.06 (q, J=7.6 Hz, 1H),4.74-4.61 (m, 2H), 2.98 (td, J=13.6, 6.4 Hz, 2H), 2.43 (s, 2H),2.37-2.17 (m, 2H), 1.61 (d, J=5.9 Hz, 4H). MS (m/z) 495 [M+H]⁺.

Example 10

Synthesis of ethyl 2-chloro-2-(o-tolylimino)acetate (10B)

The suspension of ethyl 2-oxo-2-(o-tolylamino)acetate (2.0 g, 10 mmol)and triphenylphosphine (4.0 g, 15 mmol) in carbon tetrachloride (150 mL)was refluxed overnight. The reaction was cooled down and filtered. Thefiltrate was collected and concentrated and used it without furtherpurification. MS (m/z) 226 [M+H]⁺.

Synthesis of ethyl 5-methyl-4-(o-tolyl)-4H-1,2,4-triazole-3-carboxylate(10C)

The suspension of 10B and acetohydrazide in acetonitrile was refluxedfor 2 hours. The solvent was removed. The crude product was purified byflash column (Rf: 0.2, 50% EtOAc/Hexanes). MS (m/z) 246 [M+H]⁺.

Synthesis of1-(5-methyl-4-(o-tolyl)-4H-1,2,4-triazol-3-yl)-2-phenylethanone (10D)

To a solution of 10C (1.0 g, 4.1 mmol) in toluene cooled by an ice bath,benzylmagnesium chloride (2M in THF) (3.0 mL, 6.0 mmol) was addeddropwise. After one hour, ammonia chloride solution was added to themixture and extracted with ethyl acetate (50 mL twice). The organiclayer was dried with Na₂SO₄, filtered and concentrated and used withoutfurther purification. MS (m/z) 292 [M+H]⁺.

Synthesis of1-(5-methyl-4-(o-tolyl)-4H-1,2,4-triazol-3-yl)-2-phenylethanone oxime(10E)

To a suspension of 10D and hydroxylamine hydrochloride (420 mg, 6 mmol)in ethanol (5 mL), sodium hydroxide (480 mg, 12 mmol) was added. It wasrefluxed for two hours. The reaction was acidified with 1 Nhydrochloride and extracted with ethyl acetate (50 mL twice). Theorganic layer was dried with Na₂SO₄, filtered and concentrated. Thecrude product was purified by flash column) to provide the desiredproduct. MS (m/z) 307 [M+H]⁺.

Synthesis of1-(5-methyl-4-(o-tolyl)-4H-1,2,4-triazol-3-yl)-2-phenylethanamine (10F)

The suspension of 10E (120 mg, 0.4 mmol) and zinc powder (256 mg, 4mmol) in 2 mL of acetic acid was heated to reflux for 30 minutes. Thereaction was filtered and purified on prep reverse phase HPLC using20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile).Combined pure fractions as determined by LC/MS and lyophilized toprovide the desired product. MS (m/z) 293 [M+H]⁺.

Synthesis of2-(5-hydroxy-1H-indol-3-yl)-N-(1-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-2-phenylethyl)acetamide(10G)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA(0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 10F (29.2 mg,0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction wasstirred for 2 hours. LC/MS shows desired product with a small amount ofacid. Purified reaction mixture on prep reverse phase HPLC using 20-80%B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined purefractions as determined by LC/MS and lyophilized to provide) to providethe desired product. ¹H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.64-8.42(m, 1H), 7.50-7.19 (m, 3H), 7.17-6.93 (m, 6H), 6.81 (dd, J=53.1, 21.8Hz, 4H), 6.54 (d, J=8.8 Hz, 1H), 3.39-3.22 (m, 3H), 3.09-2.85 (m, 2H),2.01 (d, J=15.7 Hz, 3H). MS (m/z) 452 [M+H]⁺.

Example 11

Synthesis ofN-(1-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(11)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL).After 10 minutes, 10F (29.2 mg, 0.1 mmol) in 0.2 mL of DMF was added tothe reaction. The reaction was stirred for 2 hours. LC/MS shows desiredproduct with a small amount of acid. Purified reaction mixture on prepreverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1%TFA/Acetonitrile). Combined pure fractions as determined by LC/MS andlyophilized to provide the desired product. ¹H NMR (400 MHz, DMSO) δ9.16-8.86 (m, 1H), 7.39 (dd, J=16.8, 8.4 Hz, 2H), 7.28 (d, J=7.2 Hz,1H), 7.16 (t, J=6.3 Hz, 3H), 6.90 (td, J=51.4, 7.6 Hz, 3H), 4.74-4.51(m, 3H), 3.10 (s, 1H), 2.94 (dd, J=13.5, 8.9 Hz, 1H), 2.44-2.10 (m, 4H),2.03 (d, J=4.7 Hz, 3H), 1.59 (s, 4H). MS (m/z) 509 [M+H]⁺.

Example 12

Synthesis of2-(5-hydroxy-1H-indol-3-yl)-N-(2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-5-yl)ethyl)acetamide(12)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA(0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 9D (26.5 mg, 0.1mmol) in 0.2 mL of DMF was added to the reaction. The reaction wasstirred for 2 hours. LC/MS shows desired product with a small amount ofacid. Purified reaction mixture on prep reverse phase HPLC using 20-80%B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined purefractions as determined by LC/MS and lyophilized to provide the desiredproduct. ¹H NMR (400 MHz, CD₃OD) δ 7.76 (s, 1H), 7.47 (t, J=7.5 Hz, 1H),7.39 (t, J=7.6 Hz, 2H), 7.21-7.01 (m, 6H), 6.96 (s, 1H), 6.84 (d, J=1.9Hz, 1H), 6.78 (d, J=6.8 Hz, 2H), 6.68 (dd, J=8.6, 2.3 Hz, 1H), 5.46 (s,2H), 5.21 (t, J=7.6 Hz, 1H), 2.96 (ddd, J=21.5, 13.3, 7.6 Hz, 2H).; MS(m/z) 438 [M+H]⁺.

Example 13

Synthesis of 3-o-tolylpicolinonitrile (13B)

The suspension of ethyl 5-bromothiazole-4-carboxylate (1.0 g, 4.5 mmol),potassium carbonate (23 mL, 0.4M in water), o-tolylboronic acid (613 mg,4.5 mmol) and tetrakis(triphenylphosphine) palladium (260 mg, 0.225mmol) in DME (40 mL) was degassed for 20 minutes. The mixture was thenheated at reflux. After 2 hours the reaction was filtered through celiteand the filtrate was extracted with EtOAc (30 mL) twice. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by flash column (Rf: 0.3 EtOAc/Hexanes=20%) toprovide the desired product. MS (m/z) 248 [M+H]⁺.

Synthesis of 2-(3,5-difluorophenyl)-1-(5-(o-tolyl)thiazol-4-yl)ethanone(13C)

To a solution of 13B (0.5 g, 2.15 mmol) in 6 mL of tetrahydrofurancooled by an ice bath, (3,5-difluorobenzyl)magnesium bromide (0.25M inether) (14.6 mL, 3.65 mmol) was added dropwise. After one hour, ammoniachloride solution was added to the mixture and extracted with ethylacetate (50 mL twice). The organic layer was dried with Na₂SO₄, filteredand concentrated. The crude product was purified by flash column (Rf:0.3 EtOAc/Hexanes=10%). to provide the desired product. MS (m/z) 330[M+H]⁺.

Synthesis of2-(3,5-difluorophenyl)-1-(5-(o-tolyl)thiazol-4-yl)ethanamine (13D)

Compound 13D was prepared according to the method presented for thesynthesis of Example 10 substituting 13C for 10D to provide to providethe desired product. MS (m/z) 331 [M+H]⁺.

Synthesis ofN-(2-(3,5-difluorophenyl)-1-(5-(o-tolyl)thiazol-4-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(13E)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA(0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 13D (33.1 mg,0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction wasstirred for 2 hours. LC/MS shows desired product. Purified reactionmixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1%TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determinedby LC/MS and lyophilized to provide the desired product. ¹H NMR (400MHz, DMSO) δ 10.46 (s, 1H), 9.18 (s, 1H), 8.31 (d, J=8.2 Hz, 1H),7.35-7.15 (m, 2H), 7.05 (t, J=7.1 Hz, 2H), 6.94 (dd, J=10.2, 5.8 Hz,2H), 6.75 (t, J=7.2 Hz, 2H), 6.59-6.35 (m, 3H), 3.38 (s, 2H), 3.01 (d,J=7.5 Hz, 2H), 1.81 (s, 3H). MS (m/z) 504 [M+H]⁺.

Example 14

Synthesis ofN-(2-(3,5-difluorophenyl)-1-(5-(o-tolyl)thiazol-4-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(14)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL).After 10 minutes, 13D (33.1 mg, 0.1 mmol) in 0.2 mL of DMF was added tothe reaction. The reaction was stirred for 2 hours. LC/MS shows desiredproduct with a small amount of acid. Purified reaction mixture on prepreverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1%TFA/Acetonitrile). Combined pure fractions as determined by LC/MS andlyophilized to provide the desired product. ¹H NMR (400 MHz, DMSO) δ9.23 (s, 1H), 8.89 (d, J=8.3 Hz, 1H), 7.35-7.16 (m, 2H), 7.11 (t, J=7.6Hz, 1H), 6.99 (t, J=9.5 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.51 (d, J=6.4Hz, 2H), 4.83-4.77 (m, 1H), 4.72 (s, 2H), 3.05 (d, J=7.7 Hz, 2H),2.46-2.21 (m, 4H), 1.87 (s, 3H), 1.61 (s, 4H). MS (m/z) 561 [M+H]⁺.

Example 15

Synthesis of 1-(2-methyl-4-phenylthiazol-5-yl)-2-phenylethanamine (15B)

Compound 15B was prepared according to the method presented for thesynthesis of Example 10 substituting 15A for 10C to provide the desiredproduct. MS (m/z) 295 [M+H]⁺.

Synthesis of2-(5-hydroxy-1H-indol-3-yl)-N-(1-(2-methyl-4-phenylthiazol-5-yl)-2-phenylethyl)acetamide(15C)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA(0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 15B (29.4 mg,0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction wasstirred for 2 hours. LC/MS shows desired product with a small amount ofacid. Purified reaction mixture on prep reverse phase HPLC using 20-80%B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined purefractions as determined by LC/MS and lyophilized to provide the desiredproduct. ¹H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.59 (d, J=7.6 Hz, 1H),7.44-7.22 (m, 5H), 7.07 (dd, J=5.5, 3.2 Hz, 4H), 6.92 (dd, J=6.5, 2.9Hz, 3H), 6.80 (d, J=2.2 Hz, 1H), 6.55 (dd, J=8.6, 2.3 Hz, 1H), 5.34 (dd,J=15.0, 7.5 Hz, 1H), 3.36 (s, 2H), 3.07 (dd, J=13.8, 7.9 Hz, 1H), 2.84(dd, J=13.5, 7.0 Hz, 1H), 2.60 (s, 3H).; MS (m/z) 468 [M+H]⁺.

Example 16

Synthesis of(S)—N-(1-(2-methyl-4-phenylthiazol-5-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(16)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL).After 10 minutes, 15B (29.4 mg, 0.1 mmol) in 0.2 mL of DMF was added tothe reaction. The reaction was stirred for 2 hours. LC/MS shows desiredproduct with a small amount of acid. Purified reaction mixture on prepreverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1%TFA/Acetonitrile). Combined pure fractions as determined by LC/MS andlyophilized to provide the desired product. ¹H NMR (400 MHz, DMSO) δ9.02 (d, J=7.8 Hz, 1H), 7.46-7.26 (m, 4H), 7.13 (t, J=6.1 Hz, 3H), 6.99(d, J=7.7 Hz, 2H), 5.37 (dd, J=14.8, 7.3 Hz, 1H), 4.68 (t, J=12.7 Hz,2H), 2.99 (ddd, J=20.2, 13.5, 7.3 Hz, 2H), 2.63 (s, 3H), 2.45-2.19 (m,4H), 1.61 (d, J=5.5 Hz, 4H).; MS (m/z) 525 [M+H]⁺.

Example 17

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethylcarbamate(17A)

To a solution of N-Boc-(L)-3,5-di-F-Phe-OH (301 mg, 1 mmol) in 5 mL ofmethylene chloride at 0° C. was added CDI (170 mg, 1.05 mmol). After 30min, benzyl hydrazide (136 mg, 1 mmol) was added. The coupling wasallowed to proceed at 0° C. for 45 min, then CBr₄ (665 mg, 2 mmol) andPPh₃ (polymer-bond, ˜3 mmol/g, 667 mg, 2 mmol) were added. Thedehydration step was allowed to proceed at 0° C. for 2 hours then atambient temperature for over a weekend. The reaction mixture wasfiltered and the filtrate purified by silica gel chromatography elutingwith EtOAc/hexanes to afford the desired product. MS (m/z): 401.9[M+H]⁺.

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(17B)

(S)-tert-Butyl2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethylcarbamate(17A, 110 mg, 0.27 mmol) was dissolved in 2.7 mL of methanol and to itwas added 0.7 mL of 4M HCl in 1,4-dioxane. The reaction mixture wasallowed to stir at ambient temperature for 1 hour and the solvent wasremoved in vacuo. The residue was purified by silica gel chromatographyeluting with methanol/methylene chloride to afford 90 mg of(S)-2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine(0.26 mmol) which was dissolved in 5 mL of DMF and to it were added2-(5-fluoro-1H-indol-3-yl)acetic acid (61 mg, 0.31 mmol) andN,N-diisopropylethylamine (0.226 mL, 1.3 mmol). The reaction mixture wascooled down to 0° C. and to it was added HATU (119 mg, 0.31 mmol). Thereaction mixture was allowed to stir at ambient temperature forovernight and then purified by reverse phase HPLC eluting withacetonitrile/water (0.1% TFA) to afford the desired product. ¹H NMR (400MHz, DMSO) δ 10.93 (s, 1H), 8.79 (d, J=8.2 Hz, 1H), 7.94-7.73 (m, 2H),7.56 (m, 3H), 7.27 (dd, J=8.7, 4.5 Hz, 1H), 7.12 (m, 2H), 7.00 (m, 3H),6.84 (td, J=9.2, 2.5 Hz, 1H), 5.44 (m, 1H),), 3.52-3.12 (m, 4H). MS(m/z): 477.1 [M+H]⁺.

Example 18

Synthesis of (S)-2-phenyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethanamine(18A)

N,N′-dicyclohexylcarbodiimide (454 mg, 2.2 mmol) was added to a solutionof benzamidooxime (272 mg, 2 mmol) and N-ethyoxycarbonyl-L-phenylalanine(475 mg, 2 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heatedunder stirring at 100° C. for 16 hours. The solvent was removed undervacuum and the residue purified by silica gel chromatography elutingwith EtOAc/hexanes to afford 280 mg of (S)-ethyl2-phenyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethylcarbamate which wasdissolved in 10 mL of ethanol and 10 mL of 10% NaOH aqueous solution.The mixture was heated up to 100° C. for 3 hours, and then cooled downto ambient temperature. After extracted with methylene chloride, theorganic layer was separated and dried over sodium sulfate, filtered andconcentrated to afford the desired product. MS (m/z): 266.1 [M+H]⁺.

Synthesis of(S)-2-(5-fluoro-1H-indol-3-yl)-N-(2-phenyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)acetamide(18B)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 18A and2-(5-fluoro-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO) δ 10.92(s, 1H), 8.90 (d, J=8.0 Hz, 1H), 7.94 (m, 2H), 7.68-7.39 (m, 3H),7.37-7.06 (m, 8H), 6.85 (td, J=9.2, 2.5 Hz, 1H), 5.34 (dd, J=13.8, 9.2Hz, 1H), 3.46-3.20 (m, 4H); MS (m/z) 441.1 [M+H]⁺.

Example 19

Synthesis of 2-(4-chlorophenyl)oxazole-5-carbaldehyde (19B)

NaN₃ (1.1 equiv) was added in one portion to an ice-cooled, stirredsolution of 2-bromo-1-(4-chlorophenyl)ethanone (23.1 g, 100 mmol) in DMF(100 mL). After stirring the suspension for 40 min to give a yellowsolution, 6 equiv of POCl₃ was then added dropwise. The temperature waswarmed to 80-90° C. and maintained at this temperature for 16 h. Thecrude product was poured into water and stirred at r.t. for 1 h,extracted with ethyl acetate, washed with water, purified by silicacolumn with DCM:acetone=100% to 5:1 to give a yellow solid which wascrystallized from petroleum ether to give a white solid. (Yield: 2 g,11%). MS (m/z) 208.1 [M+H]⁺.

Synthesis of(Z)—N-((2-(4-chlorophenyl)oxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide(19C)

The title compound was prepared according to the method presented forthe synthesis of compound 5B of Example 5 utilizing 19B and(S)-2-methylpropane-2-sulfinamide. MS (m/z) 311.1 [M+H]⁺.

Synthesis of(Z)—N-((2-(4-chlorophenyl)oxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide(19D)

The title compound was prepared as a mixture of diastereomers accordingto the method presented for the synthesis of compound 5C and 5D ofExample 5 utilizing 19C and (3,5-difluorobenzyl)magnesium bromide. MS(m/z) 439.1 [M+H]⁺.

Synthesis of1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (19E)

The title compound was prepared according to the method presented forthe synthesis of compound 5E of Example 5 utilizing 19D. MS (m/z) 335.2[M+H]++.

Synthesis ofN-(1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(19F)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 19E and2-(5-fluoro-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, CDCl₃) δ 8.21(s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.38-7.23 (m,2H), 7.16 (s, 1H), 7.05 (d, J=9.3 Hz, 1H), 6.95 (dd, J=10.3, 7.7 Hz,1H), 6.61 (t, J=9.0 Hz, 1H), 6.50 (dd, J=14.6, 7.6 Hz, 3H), 5.27 (q,J=7.4 Hz, 1H), 3.72 (s, 2H), 3.08 (dd, J=13.7, 7.1 Hz, 1H), 2.95 (dd,J=13.7, 7.4 Hz, 1H). MS (m/z) 510.1 [M+H]⁺.

Example 20

Synthesis ofN-(1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(20)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 19E and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid.¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.5 Hz,2H), 7.35 (s, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.69-6.52 (m, 3H), 5.24 (q,J=7.6 Hz, 1H), 4.69 (s, 2H), 3.09 (ddd, J=33.5, 13.7, 7.3 Hz, 2H), 2.54(m, 2H), 2.42-2.37 (m, 2H), 1.81-1.70 (m, 4H). MS (m/z) 565.1 [M+H]⁺.

Example 21

Synthesis ofN-(1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(21)

The title compound (6.0 mg) was prepared according to the methodpresented for the synthesis of compound 5F of Example 5 utilizing 19Eand 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. ¹H NMR (400MHz, DMSO) δ 11.6 (br, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.40 (s, 1H), 8.01(s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.6 Hz, 3H), 7.03 (s, 1H),6.83 (d, J=7.8 Hz, 3H), 5.08 (d, J=5.3 Hz, 1H), 3.82 (s, 3H), 3.44 (s,2H), 3.23-3.06 (m, 1H), 3.04-2.91 (m, 1H). MS (m/z) 523.1 [M+H]⁺.

Example 22

Synthesis ofN-(1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(22)

A solution of 21 (20 mg, 0.038 mmol) and KI (33 mg, 0.2 mmol) in aceticacid (5 mL) was heated in a microwave reactor at 160° C. for 10 min.After cooling to room temperature and removing the volatiles in vacuo,the resulting residue was purified by reverse phase HPLC to yield thetitle compound. ¹H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.53 (d, J=8.5Hz, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.80 (s,1H), 7.61 (d, J=8.6 Hz, 2H), 7.02 (s, 1H), 6.86 (m, 3H), 5.10 (m, 1H),3.20-3.16 (m, 1H), 3.01-2.95 (m, 1H). MS (m/z) 508.9 [M+H]⁺.

Example 23

Synthesis ofN-(1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(23)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 19E and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid. ¹H NMR (400 MHz,DMSO) δ 9.06-8.94 (m, 2H), 8.10 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.57(d, J=8.6 Hz, 2H), 7.50 (s, 1H), 7.17 (s, 1H), 6.97 (m, 3H), 5.17-4.95(m, 3H), 3.24-3.07 (m, 1H), 3.04 (dd, J=13.7, 9.7 Hz, 1H), 2.29 (s, 1H),2.22 (s, 1H). MS (m/z) 520.9 [M+H]⁺.

Example 24

Synthesis ofN-(1-(2-(4-chlorophenyl)oxazol-5-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(24)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 19E and2-(5-hydroxy-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, CDCl₃) δ 8.06(s, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.27 (m, 1H),7.08 (s, 1H), 6.87-6.76 (m, 2H), 6.60 (m, 1H), 6.47 (d, J=6.0 Hz, 2H),6.30 (s, 1H), 5.26 (d, J=7.9 Hz, 1H), 3.67 (s, 2H), 3.08-2.93 (m, 2H).MS (m/z) 508.1 [M+H]⁺.

Example 25

Synthesis of (Z)—N-hydroxycinnamimidoyl chloride (25B)

To a stirred solution of cinnamaldoxime (10 g, 68 mmol) in DMF (100 mL)at room temperature was added solid NCS (9.08 g, 68 mmol). Thesuspension was stirred at room temperature overnight. The reactionmixture was poured into ice-water, extracted with a mixture of ethylacetate and hexanes (7:3, 3×), dried with Na₂SO₄, concentrated and driedin vacuum to give the title compound.

Synthesis of (E)-4-(4-chlorophenyl)-3-styrylisoxazole (25C)

A screw-top Schlenk flask (250 mL) purged with dry nitrogen was chargedwith compound 25B (7.31 g, 40 mmol) and 4-chlorophenylacetylene (5.0 g,36.6 mmol). At room temperature, degassed 1,2-dichloroethane (100 mL)was added followed by [Cp*RuCl(cod)](450 mg, 1.18 mmol) andtriethylamine (6.38 mL, 45.8 mmol). The flask was purged with N₂ andcapped. After being stirred at room temperature for 7 h, the reactionmixture was passed through a plug of silica gel, and washed with DCM.The resulting solution was concentrated and the residue was purified bycolumn chromatography on silica gel (pure hexanes to 10:1 hexanes/EtOAc)to provide the desired compound. MS (m/z) 282.0 [M+H]⁺.

Synthesis of 4-(4-chlorophenyl)isoxazole-3-carbaldehyde (25D)

(E)-4-(4-Chlorophenyl)-3-styrylisoxazole (2 g, 7.1 mmol) was dissolvedin DCM/MeOH (20 mL/2 mL) and cooled to −78° C. The reaction was placedunder ozonolysis conditions (O₃ bubbling) until full disappearance ofstarting material. DMS (8 mL) was added and the reaction was let warm toambient temperature. After 15 h, the reaction was partitioned betweenEtOAc and H₂O. The organics were separated, washed with saturatedaqueous NaHCO₃, and dried with saturated aqueous NaCl. Solvents wereremoved in vacuo and the residue purified by column chromatography onsilica to provide the desired product: MS (m/z) 208.0 [M+H]⁺.

Synthesis of(S,E)-N-((4-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide(25E)

The title compound was prepared according to the method presented inExample 5 substituting 4-(4-chlorophenyl)isoxazole-3-carbaldehyde for 5Ato provide the desired compound: MS (m/z) 311.0 [M+H]⁺.

Synthesis of(S)—N—((S)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(25F and 25G)

The title compounds were prepared according to the method presented inExample 5 substituting 25E for 5B to provide the desired compounds: MS(m/z) (25F) 439.8 and (25G) 439.8 [M+H]⁺.

Synthesis of(S)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethanamine(25H)

The title compound was prepared according to the method presented inExample 5 substituting 25F for 5D to provide the desired compound: MS(m/z) 335.7 [M+H]⁺.

Synthesis of(S)—N-(1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(25I)

The title compound was prepared according to the method presented in thesynthesis of 5 substituting 2-(5-fluoro-1H-indol-3-yl)acetic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and 25H for 5E toprovide the desired compound. ¹H NMR (400 MHz, DMSO) δ 10.88 (s, 1H),9.06 (s, 1H), 8.72 (d, 1H), 7.26 (dd, 3H), 7.12-7.02 (m, 2H), 6.95-6.79(m, 2H), 6.73 (d, 2H), 5.29 (dd, 1H), 3.35 (s, 2H), 3.18-2.99 (m, 2H).;MS (m/z) 511.1 [M+H]⁺.

Example 26

Synthesis of(S)—N-(1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(26)

The title compound was prepared according to the method presented in thesynthesis of 19F substituting 2-(5-hydroxy-1H-indol-3-yl)acetic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and(S)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethanaminefor 19E to provide the desired compound (26): ¹H NMR (400 MHz, DMSO) δ10.46 (s, 1H), 9.04 (s, 1H), 8.65 (d, 1H), 7.35-7.20 (m, 3H), 7.06 (d,1H), 6.92 (t, 1H), 6.87 (d, 1H), 6.77 (d, 1H), 6.71 (d, 2H), 6.54 (dd,1H), 5.25 (q, 1H), 3.39-3.25 (m, 2H), 3.08 (d, 2H).; MS (m/z) 508.8[M+H]⁺.

Example 27

Synthesis of(S)—N-(1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(27)

The title compound was prepared according to the method presented in thesynthesis of 19F substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and(S)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethanaminefor 19E to provide the desired compound (27): ¹H NMR (400 MHz, DMSO) δ9.10 (s, 1H), 8.99 (d, 1H), 7.41 (d, 2H), 7.35 (d, 2H), 6.98 (d, 1H),6.80 (d, 2H), 5.36 (d, 1H), 4.58 (s, 2H), 3.12 (dt, 2H), 2.46 (dd, 2H),2.22 (d, 2H), 1.61 (s, 4H).; MS (m/z) 566.3 [M+H]⁺.

Example 28

Synthesis of(R)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethanamine(28A)

The title compound was prepared according to the method presented inExample 5 substituting 25G for 5D to provide the desired compound: MS(m/z) 335.7 [M+H]⁺.

Synthesis of(R)—N-(1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(28B)

The title compound was prepared according to the method presented in thesynthesis of 5F substituting 2-(5-hydroxy-1H-indol-3-yl)acetic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and 28A for 5E toprovide the desired compound (28B): ¹H NMR (400 MHz, DMSO) δ 10.46 (s,1H), 9.04 (s, 1H), 8.65 (d, 1H), 7.32-7.20 (m, 3H), 7.06 (d, 1H),6.95-6.83 (m, 2H), 6.74 (dd, 3H), 6.54 (dd, 1H), 5.25 (q, 1H), 3.41-3.25(m, 2H), 3.08 (d, 2H).; MS (m/z) 509.1 [M+H]⁺.

Example 29

Synthesis of 5-(4-chlorophenyl)-1-methyl-1H-imidazole (29C)

1-Chloro-4-iodobenzene (10 g, 42 mmol) was combined with1-methyl-1H-imidazole (13.3 mL, 168 mmol), Pd(OAc)₂ (470 mg), PCy₃.HBF₄(1.54 g), Cs₂CO₃ (13.7 g, 42 mmol) in DMF (200 mL). The reaction washeated to 120° C. for 15 hr. After cooling to ambient temperature, thereaction was filtered to remove solids and the eluent was partitionedbetween EtOAc and H₂O. The organics were separated, washed withsaturated aqueous NaHCO₃, and dried with saturated aqueous NaCl.Solvents were removed in vacuo and the residue purified by columnchromatography on silica to provide the desired product. MS (m/z) 193.3[M+H]⁺.

Synthesis of 4-bromo-5-(4-chlorophenyl)-1-methyl-1H-imidazole (29D)

(4-Chlorophenyl)-1-methyl-1H-imidazole (3 g, 15.5 mmol) was dissolved inACN (150 mL) and cooled to 0° C. NBS (2.76 g, 15.5 mmol) was added in 3portions over 5 min. The reaction was stirred at 0° C. for 20 min thenlet warm to ambient temperature. Solvents were removed in vacuo and theresidue partitioned between EtOAc and 20% aqueous KH₂PO₄. The organicswere separated, washed with saturated aqueous NaHCO₃, and dried withsaturated aqueous NaCl. Solvents were removed in vacuo and the residuepurified by column chromatography on silica to provide the desiredproduct. MS (m/z) 273.1 [M+H]⁺.

Synthesis of 5-(4-chlorophenyl)-1-methyl-1H-imidazole-4-carbonitrile(29E)

To 4-bromo-5-(4-chlorophenyl)-1-methyl-1H-imidazole (1.3 g, 4.79 mmol)in DMF (8.4 mL) and pyridine (1.6 mL) was added CuCN (1.3 g, 14.4 mmol).The reaction was heated in a microwave reactor at 200° C. for 35 min.After cooling to ambient temperature, the reaction was quenched byaddition of a 3:1 solution of NH₄OH/saturated aqueous NH₄Cl (60 mL). Thereaction was extracted with EtOAc, organics separated, washed withsaturated aqueous NaHCO₃, and dried with saturated aqueous NaCl.Solvents were removed in vacuo and the residue purified by columnchromatography on silica to provide desired product and recoveredstarting material. The recovered starting material was resubjected tothe reaction conditions and purified as above to provide additionaldesired product. MS (m/z) 218.3 [M+H]⁺.

Synthesis of1-(5-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-2-(3,5-difluorophenyl)ethanamine(29F)

To a solution of 5-(4-chlorophenyl)-1-methyl-1H-imidazole-4-carbonitrile(520 mg, 2.4 mmol) in toluene (13 mL) at 0° C. was added(3,5-difluorobenzyl)magnesium bromide (12.5 mL of a 0.25 M solution indiethylether). The reaction was stirred 20 min at 0° C. then let warm toambient temperature. After stirring for 40 min, the reaction was cooledto 0° C. 2-Butanol (8 mL) and MeOH (4 mL) were added followed byaddition of NaBH₄ (135 mg, 3.6 mmol) and stirred for 20 min. Thereaction was quenched by addition of saturated aqueous NH₄Cl andextracted with EtOAc. The organics were separated, washed with saturatedaqueous NaHCO₃, and dried with saturated aqueous NaCl. Solvents wereremoved in vacuo and the residue purified by column chromatography onsilica to provide the desired product. MS (m/z) 348.3 [M+H]⁺.

Synthesis ofN-(1-(5-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(29G)

The title compound as prepared according to the method presented in thesynthesis of Example 1 utilizing 29F and2-(5-fluoro-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.94(d, 1H), 8.78 (s, 1H), 8.42 (d, 1H), 7.49-7.42 (m, 2H), 7.32-7.20 (m,3H), 7.17-7.06 (m, 2H), 6.99-6.80 (m, 2H), 6.69-6.60 (m, 2H), 4.87 (q,1H), 3.49 (s, 3H), 3.41 (d, 2H), 3.08 (dd, 1H), 2.94 (dd, 1H); MS (m/z)523.3 [M+H]⁺.

Example 30

Synthesis ofN-(1-(5-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(30)

The title compound as prepared according to the method presented in thesynthesis of Example 1 utilizing 29F and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid.MS (m/z) 579.0 [M+H]⁺.

Example 31

Synthesis ofN-(1-(5-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(31)

The title compound as prepared according to the method presented in thesynthesis of Example 1 utilizing 29F and2-(5-hydroxy-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆) δ10.52 (s, 1H), 8.26 (s, 1H), 7.43 (s, 2H), 7.18 (d, 2H), 7.08 (d1H),6.99-6.92 (m, 2H), 6.73 (s, 1H), 6.64-6.52 (m, 3H), 4.85 (d, 1H), 3.47(s, 3H), 3.10-3.01 (m, 1H), 2.99-2.88 (m, 1H); MS (m/z) 521.7 [M+H]⁺.

Example 32

Synthesis ofN-(1-(5-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-(trifluoromethyl)-1H-indol-3-yl)acetamide(32)

The title compound as prepared according to the method presented in thesynthesis of Example 1 utilizing 29F and2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.31 (s, 1H), 8.52 (d, 1H), 7.81 (d, 1H), 7.46 (dd, J 2H),7.35-7.17 (m, 3H), 6.96-6.86 (m, 1H), 6.66-6.59 (m, 2H), 4.87 (q, 1H),3.49 (s, 3H), 3.07 (dd, 1H), 2.94 (dd, 1H); MS (m/z) 573.9 [M+H]⁺.

Example 33

Synthesis of ethyl 5-(4-chlorophenyl)oxazole-4-carboxylate (33C)

Triethylamine (20 mL, 144 mmol) was added to a solution of4-chlorobenzoyl chloride (8.4 g, 48 mmol) in THF (100 mL) at 0° C. Ethyl2-isocyanoacetate (6.0 g, 53 mmol) was added dropwise and the resultingsolution was stirred at room temperature for 1 h. The reaction mixturewas partitioned between EtOAc and water. The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica column with ethyl acetate and hexanes aseluents to give the desired compound. MS (m/z) 252.1 [M+H]⁺.

Synthesis of 5-(4-chlorophenyl)oxazole-4-carbaldehyde (33D)

To a solution of 33C (1.25 g, 5 mmol) in THF was added DIBAL-H (1.0 M intoluene, 10 mmol) dropwise at −70° C. The resulting solution was allowedto warm to −20° C. over 3 h. Upon completion of the reaction, saturatedaqueous NH₄Cl was added to the flask and the mixture was partitionedbetween EtOAc and water. The organic phase was washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The crude product wasused in the next step without further purification. MS (m/z) 208.1[M+H]⁺.

Synthesis of(E)-N-((5-(4-chlorophenyl)oxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide(33E)

The title compound was prepared according to the method presented forthe synthesis of compound 5B of Example 5 utilizing 33D and(S)-2-methylpropane-2-sulfinamide. MS (m/z) 311.2 [M+H]⁺.

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(33F)

The title compound was prepared as a mixture of diastereomers accordingto the method presented for the synthesis of compound 5C and 5D ofExample 5 utilizing 33E and (3,5-difluorobenzyl)magnesium bromide. MS(m/z) 438.9 [M+H]⁺.

Synthesis of1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (33G)

The title compound was prepared according to the method presented forthe synthesis of compound 5E of Example 5 utilizing 33F. MS (m/z) 335.1[M+H]⁺.

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(33H)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 33G and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid. ¹H NMR (400 MHz,dmso) δ 9.36 (d, J=8.3 Hz, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 7.63-7.53(m, 3H), 7.45 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 6.98 (d, J=8.7 Hz, 1H),6.88 (d, J=7.2 Hz, 2H), 5.36 (d, J=7.5 Hz, 1H), 5.17-5.01 (m, 2H),3.27-3.10 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H). MS (m/z) 521.1 [M+H]⁺.

Example 34

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(34)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 33G and2-(5-hydroxy-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO) δ 10.46(s, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.45 (s, 1H), 7.59 (d, J=8.4 Hz, 2H),7.43 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.6 Hz, 1H), 7.00-6.84 (m, 2H), 6.79(d, J=8.4 Hz, 3H), 6.55 (d, J=8.7 Hz, 1H), 5.28 (q, J=7.8 Hz, 1H), 3.39(s, 2H), 3.10 (m, 2H). MS (m/z) 508.1 [M+H]⁺.

Example 35

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(35)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 33G and2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. ¹H NMR (400 MHz,DMSO) δ 11.13 (s, 1H), 8.65 (d, J=8.6 Hz, 1H), 8.46 (s, 1H), 7.74 (m,1H), 7.62 (m, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.27 (s, 1H), 6.89 (t, J=9.6Hz, 1H), 6.74 (d, J=6.8 Hz, 2H), 6.60 (d, J=8.6 Hz, 1H), 5.35 (q, J=7.8Hz, 1H), 3.87 (s, 3H), 3.50 (s, 2H), 3.17-2.98 (m, 2H). MS (m/z) 523.1[M+H]⁺.

Example 36

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(36)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 33G and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid.¹H NMR (400 MHz, DMSO) δ 9.07 (d, J=8.1 Hz, 1H), 8.51 (s, 1H), 7.62 (d,J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.98 (t, J=9.6 Hz, 1H), 6.87 (d,J=7.6 Hz, 2H), 5.41-5.30 (m, 1H), 4.80-4.64 (m, 2H), 3.35 (s, 2H),3.25-3.12 (m, 1H), 3.07 (dd, J=13.4, 6.8 Hz, 1H), 2.33 (s, 1H), 2.23 (s,1H), 1.63 (s, 4H). MS (m/z) 565.1 [M+H]⁺.

Example 37

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(37)

The title compound was prepared according to the method presented forthe synthesis of compound 5F of Example 5 utilizing 33G and2-(5-fluoro-1H-indol-3-yl)acetic acid. ¹H NMR (400 MHz, DMSO) δ 10.88(s, 1H), 8.76 (d, J=8.3 Hz, 1H), 8.47 (s, 1H), 7.63 (d, J=7.9 Hz, 2H),7.43 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.8, 4.6 Hz, 1H), 7.08 (d, J=12.4Hz, 2H), 6.91-6.83 (m, 4H), 5.31 (d, J=7.9 Hz, 1H), 3.44 (s, 2H),3.22-3.11 (m, 1H), 3.06 (dd, J=13.3, 7.0 Hz, 1H). MS (m/z) 510.1 [M+H]⁺.

Example 38

Synthesis ofN-(1-(5-(4-chlorophenyl)oxazol-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(38)

The title compound was prepared according to the method presented forthe synthesis of compound 22 of Example 22 utilizing 35. ¹H NMR (400MHz, DMSO) δ 11.32 (s, 1H), 8.71 (d, J=8.0 Hz, 1H), 8.59 (s, 1H), 8.50(s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.59 (dd, J=25.7, 8.2 Hz, 2H), 7.43(dd, J=26.5, 8.2 Hz, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 6.77 (d, J=7.5 Hz,2H), 6.23 (d, J=9.2 Hz, 1H), 5.32 (d, J=7.7 Hz, 1H), 3.41 (s, 2H),3.23-3.04 (m, 2H). MS (m/z) 509.1 [M+H]⁺.

Example 39

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X′ 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X′ 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X′ 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X′ (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X′ (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X′ 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The invention has been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope of theinvention.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the present disclosure.

Alternative embodiments of the claimed disclosure are described herein,including the best mode known to the inventors for practicing theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate (e.g., altering or combiningfeatures or embodiments), and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values is stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Thus, as a generalmatter, “about” or “approximately” broaden the numerical value. Also,the disclosure of ranges is intended as a continuous range includingevery value between the minimum and maximum values plus the broadeningof the range afforded by the use of the term “about” or “approximately.”Thus, recitation of ranges of values herein are merely intended to serveas a shorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by, or derived from, any of the data disclosed hereinrepresent further embodiments of the present disclosure and are includedas part of the disclosure as though they were explicitly set forth. Thisincludes ranges that can be formed that do or do not include a finiteupper and/or lower boundary. Accordingly, a person of ordinary skill inthe art most closely related to a particular range, ratio or range ofratios will appreciate that such values are unambiguously derivable fromthe data presented herein.

1-36. (canceled)
 37. A method for treating a HIV infection in a human,comprising administering a compound of formula I:

wherein: A is a 5-membered N-heteroaryl, wherein the 5-memberedN-heteroaryl is substituted with one Z¹ group and optionally substitutedwith 1, 2, or 3 Z² groups; R¹ is a bicyclic-heteroaryl, wherein thebicyclic-heteroaryl has 4 to 12 carbon atoms and 1-5 heteroatoms, andwherein any bicyclic-heteroary of R¹ is optionally substituted with 1,2, 3, 4, or 5 Z³ groups; R² is a phenyl, 5-membered heteroaryl or6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or6-membered heteroaryl of R² is optionally substituted with 1, 2, 3, 4 or5 Z⁴ groups; Z¹ is selected from (C₃-C₈)alkyl, (C₆-C₂₀)aryl, andaryl(C₁-C₆)alkyl-, wherein any aryl and aryl(C₁-C₆)alkyl- of Z¹ isoptionally substituted with 1, 2, 3, 4, or 5 Z^(1a) or Z^(1b) groups andwherein any (C₃-C₈)alkyl of Z¹ is optionally substituted with 1, 2, 3,4, or 5 Z^(1a) groups; each Z^(1a) is independently selected from(C₃-C₇)carbocycle, halogen, —CN, —OR_(n1), —OC(O)R_(p1),—OC(O)NR_(q1)R_(r1), —SR_(n1), —S(O)R_(p1), —S(O)₂OH, —S(O)₂R_(p1),—S(O)₂NR_(q1)R_(r1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1),—NR_(n1)CO₂R_(p1), —NR_(n1)CONR_(q1)R_(r1), —NR_(n1)S(O)₂R_(p1),—NR_(n1)S(O)₂OR_(p1), —NR_(n1)S(O)₂NR_(q1)R_(r1), NO₂, —C(O)R_(n1),—C(O)OR_(n1) and —C(O)NR_(q1)R_(r1); each Z^(1b) is independentlyselected from (C₁-C₆)alkyl and (C₃-C₅)carbocycle wherein any(C₁-C₆)alkyl and (C₃-C₅)carbocycle of Z^(1b) is optionally substitutedwith 1, 2, 3, 4, or 5 halogen; each Z² is independently selected from(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, halogen and —O(C₁-C₃)alkyl; each Z³ isindependently selected from (C₁-C₆)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR_(n2), —OC(O)R_(p2), —OC(O)NR_(q2)R_(r2), —SR_(n2), —S(O)R_(p2),—S(O)₂OH, —S(O)₂R_(p2), —S(O)₂NR_(q2)R_(r2), —NR_(q2)R_(r2),—NR_(n2)COR_(p2), —NR_(n2)CO₂R_(p2), —NR_(n2)CONR_(q2)R_(r2),—NR_(n2)S(O)₂R_(p2), —NR_(n2)S(O)₂OR_(p2), —NR_(n2)S(O)₂NR_(q2)R_(r2),NO₂, —C(O)R_(n2), —C(O)OR_(n2) and —C(O)NR_(q2)R_(r2), wherein any(C₃-C₇)carbocycle and (C₁-C₆)alkyl of Z³ is optionally substituted with1, 2, 3, 4, or 5 halogen; each Z⁴ is independently selected from(C₁-C₆)alkyl, halogen and —OR_(n3), wherein any (C₁-C₆)alkyl of Z⁴ isoptionally substituted with 1, 2, 3, 4, or 5 halogen; each R_(n1) isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl and (C₃-C₇)carbocycle; each R_(p1) is independentlyselected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and(C₃-C₇)carbocycle; R_(q1) and R_(r1) are each independently selectedfrom H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and(C₃-C₇)carbocycle, or R_(q1) and R_(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle; eachR_(n2) is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl and (C₃-C₇)carbocycle; each R_(p2) is independentlyselected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and(C₃-C₇)carbocycle; R_(q2) and R_(r2) are each independently selectedfrom H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and(C₃-C₇)carbocycle, or R_(q2) and R_(r2) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle; and eachR_(n3) is independently selected from H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,and (C₃-C₇)carbocycle; or a pharmaceutically acceptable salt thereof, tothe human.
 38. The method of claim 37, wherein A is selected fromimidazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, thiazol-4-yl,thiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, oxazol-5-yl,isoxazol-3-yl, imidazol-4-yl and oxazol-4-yl, wherein imidazol-2-yl,1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, thiazol-4-yl, thiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, oxazol-5-yl, isoxazol-3-yl,imidazol-4-yl and oxazol-4-yl are each substituted with one Z¹ group andoptionally substituted with 1, 2, or 3 Z² groups.
 39. The method ofclaim 37, wherein A is:

wherein the dashed bond is a single or double bond so that ring A isaromatic, A is substituted with one Z¹ group and optionally substitutedwith 1, 2, or 3 Z² groups.
 40. The method of claim 37, wherein A is:

wherein the dashed bonds are single or double bonds so that ring A isaromatic, X is N or C, and wherein A is optionally substituted with 1,2, or 3 Z² groups.
 41. The method of claim 37, wherein A is:

wherein X is N or C, each X¹ is independently selected from N, NZ^(2a),O, S and CZ^(2a), the dashed bonds are selected from single and doublebonds so that ring A is aromatic, and Z^(2a) is selected from H and Z².42. The method of claim 37, wherein A is selected from

wherein each Z^(2a) is independently selected from Z² and H.
 43. Themethod of claim 37, wherein each Z^(1a) is independently selected fromhalogen and —OR_(n1), each Z^(1b) is (C₁-C₆)alkyl, and wherein R_(n1) is(C₁-C₆)alkyl.
 44. The method of claim 37, wherein A is selected from


45. The method of claim 37, wherein R² is phenyl optionally substitutedwith 1, 2, 3, 4, or 5 Z⁴ groups.
 46. The method of claim 37, whereineach Z⁴ is halogen.
 47. The method of claim 37, wherein R¹ is selectedfrom indolyl, 4,5,6,7-tetrahydro-indazolyl, benzo[d]imidazolyl andpyrrolo[3,2-b]pyridinyl, wherein any indolyl,4,5,6,7-tetrahydro-indazolyl, benzo[d]imidazolyl andpyrrolo[3,2-b]pyridinyl of R¹ is optionally substituted with 1, 2, 3, 4,or 5 Z³ groups.
 48. The method of claim 37, wherein each Z³ isindependently selected from fluoro, hydroxy, trifluoromethyl, methyl andmethoxy.
 49. The method of claim 37, wherein R¹ is selected from:


50. The method of claim 37, wherein the compound of formula I isselected from:

and pharmaceutically acceptable salts thereof.
 51. The method of claim37, wherein the compound of formula I is administered in apharmaceutical composition comprising the compound of formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 52. The method of claim 37, wherein the compound offormula I, or a pharmaceutically acceptable salt thereof, isadministered in combination with one or more additional therapeuticagents selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof.